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Lai C.-Y.,China Medical University at Taichung | Sung F-C.,China Medical University at Taichung | Hsieh L.-L.,Chang Gung University | Tang R.,Colorectal Section | And 4 more authors.
Annals of Surgical Oncology | Year: 2013

Purpose. This retrospective cohort study investigated the association between epidermal growth factor receptor (EGFR) polymorphisms and clinical outcomes in colorectal cancer (CRC) patients treated with 5-fluorouracil (5-FU)-based chemotherapy. Methods. We genotyped 3 EGFR polymorphisms including R497K, G-216T, and the (CA)n repeat, among 499 histologically confirmed CRC patients who had received 5-FU-based chemotherapy after surgery between 1995 and 2001. Survival analyses of EGFR polymorphisms were performed by the log rank test and Kaplan-Meier curves. We used the Cox proportional hazard model to evaluate the association between EGFR genotypes and clinical outcomes. Stratification analysis by gender, tumor stage, and subsite were also carried out. Results. CRC patients with the EGFR (CA)n L/L genotype compared to those with the S/S?S/L genotype had a significantly better overall survival (L, C20 repeats; S,\20 repeats) (hazard ratio (HR) 0.74; 95 % confidence interval (CI) 0.57-0.95), particularly for patients who were male (HR 0.63; 95 % CI 0.44-0.90), who had stage IV disease (HR 0.70; 95 % CI 0.49-0.99), and who had rectal cancer (HR 0.62; 95 % CI 0.42-0.92). Better survival was prominent among patients with the combined genotypes of EGFR (CA)n L/L, G-216T G/G, and R497K K/K (HR 0.51; 95 % CI 0.30-0.87), compared to those with the most common genotypes of the EGFR (CA)n S allele, G-216T G/G, and R497K R allele. Conclusions. EGFR polymorphisms can serve as prognostic predictors for CRC patients receiving 5-FU-based chemotherapy. © Society of Surgical Oncology 2012.

Lai C.-Y.,China Medical University at Taichung | Hsieh L.-L.,Chang Gung University | Sung F.-C.,China Medical University at Taichung | Tang R.,Colorectal Section | And 5 more authors.
PLoS ONE | Year: 2013

Introduction:Our retrospective cohort study investigated the effect of tumor site and stage on the associations between the allelic variants of glutathione S-transferase (GST) and DNA-repair genes and overall survival (OS) in CRC patients treated with 5-fluorouracil (5-FU)-based adjuvant chemotherapy.Material and Methods:We genotyped GSTM1, GSTT1, GSTP1 Ile105Val, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln in 491 CRC patients between 1995 and 2001. A Cox proportional-hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationships between the allelic variants and OS. Survival analyses were performed for each allelic variant by using the log-rank test and Kaplan-Meier analysis.Results:The CRC patients with the XPD Gln allelic variants had poorer survival than patients with the Lys/Lys genotype (HR = 1.38, 95% CI = 1.02-1.87), and rectal cancer patients had the poorest survival among them (HR = 1.87, 95% CI = 1.18-2.95). A significantly shorter OS was observed among stage II/III colon cancer patients with the XRCC1 Gln allelic variants (HR = 1.69, 95% CI = 1.06-2.71), compared to those with XRCC1 Arg/Arg genotype. In the combined analysis of the XRCC1 and XPD genes patients with stage II/III tumors, the poorest OS occurred in colon cancer patients with the XRCC1 Gln and XPD Gln allelic variants (HR = 2.60, 95% CI = 1.19-5.71) and rectal cancer patients with the XRCC1 Arg/Arg and XPD Gln allelic variants (HR = 2.77, 95% CI = 1.25-6.17).Conclusion:The XPD and XRCC1 allelic variants may be prognostic markers for CRC patients receiving 5-FU based chemotherapy. The contributions of the XPD and XRCC1 allelic variants to OS are tumor site- and/or stage-dependent. © 2013 Lai et al.

Yeh C.-C.,China Medical University at Taichung | Lai C.-Y.,China Medical University at Taichung | Hsieh L.-L.,Chang Gung University | Tang R.,Colorectal Section | And 2 more authors.
Carcinogenesis | Year: 2010

Oxidative stress has been associated with the carcinogenesis of colorectal cancer. Glutathione S-transferases (GSTs) modulate the elimination of free radical.We conducted a case-control study to examine the interaction between oxidative stress and GSTs polymorphisms on colorectal cancer risk. This study recruited 727 pathologically confirmed colorectal adenocarcinoma cases and 736 sex- and age-matched controls. Plasma protein carbonyls, as a parameter of oxidative stress, were measured using enzymelinked immunosorbent assay. Genotypes of GSTM1, GSTT1 and GSTP1 genes were determined using polymerase chain reaction methods. The protein carbonyl levels were significantly higher in cases than in controls and exerted a dose-response relationship (P for trend < 0.001). Compared with the first carbonyl quartile subjects, those in the second, third and fourth quartiles had odds ratios (ORs) of 1.54 [95% confidence interval (CI) = 1.13-2.10], 1.52 (95% CI = 1.11-2.07) and 1.98 (95% CI = 1.46-2.67), respectively. This effect was significantly modified by GSTM1 genotype (P for interaction = 0.037). The three-way interaction analysis revealed that interactions between GSTM1 genotype and cigarette smoking and between GSTT1 genotype and alcohol drinking further modified the oxidative stress contribution for colorectal cancer (p for interaction were 0.067 and 0.054, respectively). The impact of oxidative stress was more prominent among eversmokers with GSTM1-null genotype (OR = 3.45, 95%CI = 1.70- 6.97) and ever-drinkers with GSTT1-present genotype (OR = 3.87, 95% CI = 1.82-8.25). Our results indicate that interaction between oxidative stress and GSTs polymorphisms may play an important role in the pathogenesis of colorectal cancer. © The Author 2009. Published by Oxford University Press.

Chen Y.-J.,Academia Sinica, Taiwan | Chen Y.-J.,National Taiwan University | Ching W.-C.,Academia Sinica, Taiwan | Ching W.-C.,A-Life Medical | And 9 more authors.
Journal of Proteome Research | Year: 2014

The abnormal S-nitrosylation induced by the overexpression and activation of inducible nitric oxide synthase (iNOS) modulates many human diseases, such as inflammation and cancer. To delineate the pathophysiological S-nitrosoproteome in cancer patients, we report an individualized S-nitrosoproteomic strategy with a label-free method for the site-specific quantification of S-nitrosylation in paired tumor and adjacent normal tissues from 11 patients with colorectal cancer (CRC). This study provides not only the first endogenous human S-nitrosoproteomic atlas but also the first individualized human tissue analysis, identifying 174 S-nitrosylation sites in 94 proteins. Fourteen novel S-nitrosylation sites with a high frequency of elevated levels in 11 individual patients were identified. An individualized S-nitrosylation quantitation analysis revealed that the detected changes in S-nitrosylation were regulated by both the expression level and the more dramatic post-translational S-nitrosylation of the targeted proteins, such as thioredoxin, annexin A4, and peroxiredoxin-4. These endogenous S-nitrosylated proteins illustrate the network of inflammation/cancer-related and redox reactions mediated by various S-nitrosylation sources, including iNOS, transnitrosylase, or iron-sulfur centers. Given the demonstrated sensitivity of individualized tissue analysis, this label-free approach may facilitate the study of the vastly under-represented S-nitrosoproteome and enable a better understanding of the effect of endogenous S-nitrosylation in cancer. © 2014 American Chemical Society.

De Santibanes E.,Hepato Pancreato Biliary and Liver Transplant Sections | Fernandez D.,Hepato Pancreato Biliary and Liver Transplant Sections | Vaccaro C.,Colorectal Section | Quintana G.O.,Colorectal Section | And 4 more authors.
World Journal of Surgery | Year: 2010

Background We evaluated the simultaneous resection of colorectal malignancies and synchronous liver metastases. Methods Between June 1982 and June 2006, a total of 752 patients underwent resection of colorectal hepatic metastases. In all, 185 (25%) of them underwent simultaneous resection of the hepatic lesions and the corresponding primary tumors. Results The median hospital stay was 8 days (range 4- 24 days), with a median operating time of 4 h (range 2-8 h). Altogether, 62 (33.5%) patients required intraoperative transfusion of packed red blood cells (median 2.1 IU, range 1-5 IU), and 25 (13.5%) were given frozen fresh plasma (median 2.1 IU, range 1-4 IU). The morbidity rate was 20.5%. There were two postoperative deaths (mortality rate 1.08%) within 30 days of the surgical intervention. Major hepatectomy was associated with greater morbidity (37.2% vs. 16.2%, P<0.01) and mortality (4.7% vs. 0%, P<0.05) rates. For the overall survivals (OS) at 3 and 5 years were 60.1% (52.3-67.85%) and 36.1% (27.4-44.8%), respectively. Disease-free survivals (DFS) at 3 and 5 years were 37.7% (30.2-45.3%) and 26.5% (18.7-34.3%), respectively. Transfusion of blood products, CEA level ≥ 200 ng/dl, and N2 node status were found to be prognostic factors by univariate analysis. CEA level ≥ 200 ng/dl and N2 node status achieved prognostic significance by multivariate analysis. Conclusions The simultaneous resection of colorectal malignancies and synchronous livermetastases is safe, avoids an additional intervention, can be performed with low morbidity and mortality, and is associated with good oncologic outcomes.Node stage N2 and CEA level ≥ 200 ng/dl should be given special consideration when selecting patients. © Société Internationale de Chirurgie 2010.

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